Extending the Interpretation of Biomarker Dynamics in <scp>SOD1</scp> ‐ <scp>ALS</scp> Proteomics

We read with great interest the article by Steffke et al1 describing novel therapy-responsive biomarkers in SOD1-ALS using targeted proteomics. The longitudinal design and scope of biomarker coverage are excellent. We present three further considerations to enhance interpretation and translational impact. First, the protracted elevation of pro-inflammatory cytokines at 12 months may be because of drug- or procedure-related processes and not disease biology. Tofersen real-world data reveal cerebrospinal fluid (CSF) pleocytosis and intrathecal immunoglobulin synthesis on treatment.2 Careful<zaq;5> scheduling of sample collection exactly with dosing cycles and regular CSF indices reporting (cell count, protein, and oligoclonal bands) would enable iatrogenic versus disease-driven inflammation separation, which is important for both safety monitoring and biomarker validity in therapeutic trials. Second, the male-specific decrease in Aβ1-40 and Aβ1-42 is in need of mechanistic follow-up. Sex hormones, with estrogen being a key example, influence APP processing, Aβ metabolism, and neuroinflammation.3, 4 The inclusion of sex as an interaction term in longitudinal models and the recording of menopausal or hormone-replacement status, might establish whether Aβ peptides are reliable pharmacodynamic readouts across patient populations, which are crucial for biomarker-driven trial design. Third, neuropentraxin proteins (NPTX1, NPTX2, and NPTXR) associated with Amyotrophic Lateral Sclerosis (ALS) Functional Rating Scale (ALSFRS-R) change, but not neurofilaments. As has been argued elsewhere,5 based on their association with synaptic health and TDP-43 pathology, as well as prognostic value in ALS populations, neuropentraxins merit prospective validation as add-on or in certain settings, alternative, pharmacodynamic endpoints. Such a prioritization might enhance signal detection in early-phase trials. These additions seek to supplement, not duplicate, the authors' discussion and to emphasize analytic nuances of direct utility to ALS drug development. Hammad Khan: Writing – original draft; writing – review and editing; supervision; methodology. Muhammad Mustafa Khan: Conceptualization; writing – original draft.